Current approaches for the treatment of primary malignant glioma (GBM) are largely unsuccessful, with most GBM recurring at or adjacent to their site of origin, indicating a failure to eradicate local tumor growth; moreover, these treatments lack tumor specificity, frequently inducing normal brain toxicity, resulting in decline in quality of life. Our hypothesis is that these limitations can be overcome by combining a GBM reactive monoclonal antibody (MAb) with a radionuclide emitting highly cytotoxic and focal radiation. Our clinical goal is to evaluate the therapeutic potential of 211At-labeled anti-tenascin MAb 81C6 in newly diagnosed GBM patients. Astatine-211 emits -particles that have a greater cytotoxic effectiveness and are less susceptible to resistance than conventional radiation, and have a range in tissue of only a few cell diameters, characteristics that can offer important advantages for brain tumor treatment. In our pilot study performed with chimeric 81C6 (ch81C6) labeled via N-succinimidyl 3-[211At]astatobenzoate (SAB) in recurrent brain tumor patients, encouraging responses were obtained with minimal toxicity, with 2 GBM patients surviving for nearly 3 years. However, the maximum tolerated dose was not determined because of radiolysis-induced problems with 211At labeling at higher activity levels. Basic radiochemistry investigations over the past few years have now yielded a solution to this problem. In parallel, our preclinical goal is to lay the groundwork for eventual clinical evaluation of 211At-labeled ch81C6 combined with MAb labeled with a low-energy -emitter to extend the zone of therapeutic effectiveness beyond the SCRC interface. Our Specific Aims are: 1) To complete radiochemistry studies optimizing labeling of ch81C6 with 211At at the activity levels needed for reliable dose escalation; 2) to conduct a Phase I/II clinical trial of 211At-labeled ch81C6 administered into the SCRC of newly diagnosed GBM patients, with the Phase 1 study done at escalating doses of 211At (mCi) and the Phase II dose at a targeted radiation dose (Gy) to the SCRC margins; 3) to evaluate efficacy and normal tissue toxicity of an anti-tenascin 81C6 combination therapy approach utilizing the -particle emitter 211At and either the -particle emitter 177Lu or 131I.